The Specific Aim of this Phase I study is to evaluate whether vagus nerve stimulation (VNS) can enhance fear extinction. Exposure Therapy in humans is a form of fear extinction. Exposure therapy is the primary tool used to treat posttraumatic stress disorder (PTSD). About 8% of the US population suffers from PTSD. PTSD is currently an unmet medical need;in fact about 30-50% of PTSD sufferers are refractory to all current forms of treatment. PTSD is marked by dramatic and incapacitating stress in response to stimuli that are reminders of a trauma. Effective Exposure Therapy depends upon extinction of old associations and learning of new associations. The implicit assumption is that repeated exposure trains the patient to make neutral or positive associations with the reminders of their stressful episodes. Exposure therapy is therefore a type of fear extinction, which relies on learning and memory. Interestingly, VNS enhances memory in humans and treatment with memory-enhancing drugs appears to be an effective adjunct to Exposure Therapy. In addition, VNS reduces anxiety in people. Therefore, VNS offers the benefit of anxiety relief while enhancing memory. These are two key aspects of effective Exposure Therapy. These observations have led us to propose to use VNS paired with Exposure Therapy as a way to enhance the low success rate of Exposure Therapy. To accomplish our Specific Aim, we will evaluate whether VNS enhances the rate at which rats stop exhibiting fear responses to conditioned cues. If we can enhance the rate of extinction of fear responses in rats, it may be possible to enhance the effectiveness of Exposure Therapy in humans. In our first experiment we will examine whether VNS facilitates extinction in fear-conditioned rats. In our second experiment, we will examine the effect of VNS when given two weeks after the initial fear conditioning. PTSD can take time to develop, so potential treatments must also be effective when initiated after memory consolidation of an initial trauma has taken place. In our third experiment, we will examine whether VNS-facilitated memory extinction effects are long-lasting. Because the spontaneous recovery of fear memories after extinction has been observed in human and non-human animals, it is important to examine whether the effects of VNS treatment are long-lasting. In order for Phase I to be considered feasible, we must observe significant effects of VNS stimulation in all three of the above experimental situations. This test of feasibility will show that VNS can reduce fear responses and the effect is long-lasting. These observations would suggest that such a treatment might be relevant to humans with PTSD. In Phase II we will carry out additional studies aimed at testing this rehabilitation method in humans. PUBLIC HEALTH RELEVANCE: The proposed research aims to examine whether vagus nerve stimulation might enhance the effectiveness of Exposure Therapy in the treatment of posttraumatic stress disorder (PTSD).